This proposal responds to RFA-NS-19-029 to address the need for better evidence-based pain treatment for patients with chronic low back pain (CLBP) who have co-occurring negative affective disorders, such as major depression with anxious features. The CLBP subgroup with comorbid depression or anxiety disorders (commonly termed, high negative affect) is approximately 20-30% of the 50 million adults with CLBP in this country. This subgroup is particularly refractory to pain treatment and is in desperate need of better non- opioid, comprehensive pain treatment options. Patients with CLBP and high levels of negative affect (NA) suffer higher levels of pain and have worse disability and function. Due to these factors they are prescribed opioids more frequently and misuse opioids at a much greater rate (40-60% rates of non-adherence), which is related to self-medication of depression and anxiety by taking extra opioids. Poor pain management in patients with high NA is due in part to a lack of more effective evidenced-based treatment options to improve pain, depression, anxiety, and function, and prevent opioid misuse. We have shown in separate RCTs in CLBP patients with high NA that antidepressants (AD) or ?fear avoidance based physical therapy? improve pain, function, depression, and anxiety. In this proposal we will also present data showing that the combination of antidepressants + fear avoidance PT is more efficacious than each treatment alone or a control condition. Moreover, we have also tested an enhanced fear avoidance rehabilitation protocol (EFAR) to improve outcomes further, and we found it more effective than usual care. To address the unmet needs of CLBP patients with high negative affect, we propose to test in a randomized trial if the combination of AD+EFAR is more effective than each treatment alone to improve pain, function, depression, and prevent opioid misuse (3- arms, in 300 subjects). To better identify responders to components of the intervention (AD or EFAR), we will use an adaptive design whereby non-responders to each treatment are re-randomized to receive the other treatment. This multimodal, combination approach of pharmacotherapy +behavioral therapy is novel to the field and has the potential to shift current treatment paradigms. We will also show that the community practice environment is poised to make this shift rapidly as well. The primary outcomes are a measure of combined clinically meaningful changes in pain and self-reported function (Combined Response), and the rate of 50% improvement in depression symptoms (Depression Response) at 4 months vs. baseline. We track outcomes for a total of 8 months. The main secondary outcome is the proportion of drug misuse in each treatment group. Additional secondary outcomes include changes in sleep quality, activity levels, anxiety, craving, and opioid dose. Our anticipated findings will provide high quality evidence supporting the combined use of AD+EFAR in the prevalent group of CLBP patients with high NA. We will also identify which phenotypic subgroups of patients may best respond to just AD or EFAR alone.